The goal of this project is to investigate the genetic contribution of estrogen receptor and related genes to atherosclerotic cardiovascular disease (CVD) status and outcomes in the Framingham Heart Study, and to the response to post-myocardial infarction (MI) treatment with a selective estrogen response modulator (SERM). To address these questions, we will identify variations in genes that encode proteins that play a significant role in response to estrogen, and will test the relationship between these variants and specific clinical parameters relevant to CVD, MI and recovery from ischemic heart disease. Initially we will carry out a systematic screen for genetic variation in four genes: estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta), aromatase (the enzyme responsible for local conversion of testosterone to 17-beta estradiol), and SRC-1 (the prototypical estrogen receptor transcription co-activator). We will study the frequency of each variant in relation to specific parameters of cardiovascular function in 1,000 men and 1,000 women drawn from randomly selected population, the Framingham Offspring Study. These studies will permit an evaluation of the relationship between genotype for key genes involve din estrogen response and cardiovascular function. Furthermore, because this population has been examined longitudinally, cardiovascular function. Furthermore, because this population has been examined longitudinally, cardiovascular parameters measured on the same individual pre- and post- menopausally can be compared supporting the study of associations between genotype and post-menopausal changes in cardiovascular parameters. The study of a normal, unselected population will be complemented by investigation of the genetic contribution to parameters of response to treatment by a selective estrogen receptor modulator (SERM), raloxifene, using the study population of 150-200t-MI women from the clinical trial described in Project 2 of this SCOR proposal. In the post-MI population we will also evaluate the role of additional variants in a set of genes that are likely to play a significant role in determining cardiovascular response. This set of genes will include those for the vasodilator enzymes endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS), the vasoconstrictor, endothelin-1, the vascular endothelial growth factor (VEGF), monocyte chemotactic protein (MCP- 1), the matrix proteins collagen and matrix metalloproteinase 2 (MMP-2), the calcium-activated potassium channel, (BKCa). These studies will provide a framework for evaluating and understanding the genetic contribution to estrogen based cardiovascular protection, pathology and response to treatment.